The major object of this project is to determine the relationship between the deiodination of thyroxine (T4), in particular its monodeiodination to 3,5,3'-triodothyronine (T3), and the physiological action of the hormone, in the rat pituitary gland. Experiments will be performed using the isolated pituitary gland incubated in vitro. Under these conditions, the gland metabolizes T4 and releases TSH into the medium. The inhibition of this release by T4 or T3 can also be demonstrated. Studies will be carried out first to determine whether or not T4 is monodeiodinated to T3; a detailed search for T3 will be made. The characteristics of the deiodination system will also be assessed. The influence of hypothalamic thyrotropin-releasing hormone (TRH) on the metabolism of T4 and T3 will then be investigated. TRH will be added in vitro and its effect on both thyroid hormone metabolism and the release of TSH will be determined. Experiments will next be performed in which a concomitant study of the action of T4 in pituitary, as determined by the suppression of TSH release, and the rate of metabolism of the hormone will be made. T4 will be added in concentrations which both partially and completely inhibit TSH release, and pituitary glands from normal, thyroidectomized and TRH-treated animals will be employed. The effect on both T4 action and metabolism of adding TRH to the T4-suppressed gland and of adding compounds which prevent the suppressive action of T4 will be determined. Studies will also be performed using substances known to inhibit the deiodination of T4 in peripheral tissues. The effect of such compounds on the metabolism of the thyroid hormones in the pituitary will be determined and their possible concomitant effect on thyroid hormone action investigated. In all experiments, T4 and T3 metabolism will be examined from both the quantitative and qualitative standpoints.